Optimal design of efficacious transdermal delivery systems requires an understanding of transport mechanism(s) through skin, especially the stratum corneum barrier, and potential drug metabolism in the presence of the vehicles. While the immediate goal is directed toward understanding the mechanism(s) of solvent-enhanced percutaneous absorption of steroids, topical and transdermal system development for growth factors, polypeptides or other pharmaceutical agents would also benefit from a delivery mode that takes advantage of controlled delivery and by-passing first past metabolism. Solvent-mediated percutaneous enhancement mechanisms derived from proposed investigation will provide a systematic understanding of how common solvents employed in most formulations alter permeation pathways and barriers as a function of solvent chemical structure and physicochemical parameters. Such knowledge will provide a rational basis for formulation of a wide variety of topical and transdermal pharmaceutical systems. The working hypothesis is that there are two competing mechanisms of solvent-mediated enhanced permeation: 1) increased solubility of the solute within the vehicle or skin and 2) solvent-induced alterations of the stratum corneum membrane. The first mechanism is believed to be the primary mechanism for lipophilic solute permeation, while the second mechanism is believed to dominate for more hydrophilic solute permeation. Hence, proposed studies focus on elucidating penetration enhancer effects on the heterogeneous lipid domain, polar head regions and intracellular keratinized and cell envelope proteins within the stratum corneum; and then subsequent correlations of these biophysical alterations with in vitro and in vivo transport and metabolism across the skin. This will be achieved with the specific aims using an iterative process of probing vehicle effects on 1) solute solubility and uptake, 2) in vitro and in vivo transport via lipophilic and polar pathways and 3) alterations of biophysical structures characteristic of lipophilic and polar pathways and barriers of the stratum corneum, and 4) refinement of the mechanisms for solvent-mediated percutaneous transport and metabolism.